Aprepitant

The main ingredient of this product is aprepitant, chemical name: 5-[[(2R,3S)[[(2R,3S)[[(2R,3S)-2-[(1R)[(1R)-1-[3,5[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one; molecular formula: C23H21F7N4O3 molecular weight: 534.43534.43.

Aprepitant is a substrate, mild to moderate (dose-dependent) inhibitor and inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Drug interaction data are all from foreign studies. In a domestic clinical study, higher exposure levels of aprepitant were observed in Chinese patients. Clinically relevant drug interactions must be carefully monitored. Effect of Aprepitant on the Pharmacokinetics of Other Drugs As a moderate (125mg/80mg) inhibitor of CYP3A4, aprepitant can increase the plasma concentrations of oral drugs metabolized by CYP3A4. Aprepitant (125mg/80mg) can also increase the plasma concentrations of intravenous drugs metabolized by CYP3A4, but to a lesser extent than oral drugs. This product should not be used in combination with pimozide, terfenadine, astemizole, or cisapride. Aprepitant's dose-dependent inhibition of CYP3A4 can lead to increased plasma concentrations of these drugs, which may lead to serious or life-threatening reactions (see "Contraindications"). Studies have shown that aprepitant can induce the metabolism of S(-)warfarin and tolbutamide, which are metabolized by CYP2C9. Co-administration of aprepitant with these drugs and other drugs known to be metabolized by CYP2C9, such as phenytoin, may result in decreased plasma concentrations of these drugs. There is no interaction between aprepitant and drugs that are substrates of the P-glycoprotein transporter because no interaction was shown between aprepitant and digoxin in clinical drug interaction studies. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant had no clinically significant effect on the pharmacokinetics of ondansetron, granisetron, or hydroxydolasetron (the active metabolite of dolasetron). Glucocorticoids: Dexamethasone: Co-treatment with aprepitant 125 mg and oral dexamethasone 20 mg on day 1 and with aprepitant 80 mg daily and oral dexamethasone 8 mg on days 2 to 5 resulted in a 2.2-fold increase in the AUC of the CYP3A4 substrate dexamethasone on days 1 and 5. Therefore, if used in combination with aprepitant (125 mg/80 mg regimen), the usual oral dose of dexamethasone should be reduced by approximately 50% to achieve dexamethasone exposure levels similar to those without aprepitant. In clinical studies of aprepitant for the prevention of chemotherapy-induced nausea and vomiting, the daily dose of dexamethasone was reduced by approximately 50% (see Dosage and Administration). Methylprednisolone: Oral aprepitant 125 mg on day 1 and 80 mg daily on days 2 to 3 increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold and 2.5-fold on days 1 and 3, respectively, with a dosing regimen of 125 mg on day 1, intravenous infusion, and 40 mg orally on days 2 and 3. Therefore, when used in combination with aprepitant (125 mg/80 mg regimen), the conventional intravenous dose of methylprednisolone must be reduced by approximately 25%, while the conventional oral dose of methylprednisolone should be reduced by approximately 50% to achieve methylprednisolone exposure levels similar to those without aprepitant. Chemotherapeutic drugs: In clinical studies, aprepitant (125 mg/80 mg regimen) was co-administered with the following chemotherapeutic drugs that are primarily or partially metabolized by CYP3A4: etoposide, vinorelbine, docetaxel, and paclitaxel, and no dose adjustment of these drugs was required based on potential drug interactions. In domestic clinical studies, the number of patients receiving CYP3A4 substrates vinblastine and vincristine was small, so the information on interactions with these drugs was limited. Given the high exposure levels of aprepitant observed in Chinese patients in domestic clinical studies, special attention must be paid to monitoring the safety of patients receiving vinblastine and vincristine or other chemotherapeutic drugs metabolized by CYP3A4. Docetaxel: In a separate pharmacokinetic study, aprepitant (125 mg/80 mg therapy) did not affect the pharmacokinetics of docetaxel. Vinorelbine: In a separate pharmacokinetic study, aprepitant (125 mg/80 mg therapy) did not affect the pharmacokinetics of vinorelbine. Warfarin: In healthy subjects who were stable on long-term warfarin therapy, aprepitant 125 mg was administered orally as a single dose on day 1 and 80 mg was administered orally daily on days 2 and 3. Although aprepitant had no effect on the plasma AUC of R(-) or S(-) warfarin measured on day 3, trough concentrations of S(-) warfarin (CYP2C9 substrate) decreased by 34% and prothrombin time (reported as international normalized ratio or INR) decreased by 14% within 5 days after the end of aprepitant treatment. Therefore, in patients receiving long-term warfarin therapy, the prothrombin time (INR) must be closely monitored for 2 weeks, especially within 7 to 10 days, after each chemotherapy cycle of 3-day aprepitant. Tolbutamide: After a single oral dose of tolbutamide 500 mg before 3-day aprepitant treatment and on days 4, 8, and 15, the AUC of tolbutamide (CYP2C9 substrate) was reduced by 23%, 28%, and 15% on days 4, 8, and 15, respectively. Oral contraceptives: Coadministration of aprepitant 100 mg capsules once daily for 14 days with an oral contraceptive containing 35 ug ethinyl estradiol and 1 mg norethindrone reduced the AUC of ethinyl estradiol by 43% and the AUC of norethindrone by 8%. In another study, an oral contraceptive containing ethinyl estradiol and norethindrone was taken once daily on days 1 to 21, aprepitant 125 mg was taken orally on day 8, aprepitant 80 mg was taken orally on days 9 and 10, ondansetron 32 mg was given intravenously on day 8, and dexamethasone 12 mg was given orally as a single dose, and dexamethasone 8 mg was given orally on days 9, 10, and 11. In this study, the AUC of ethinyl estradiol decreased by 19% on day 10, and trough concentrations of ethinyl estradiol decreased by 64% on days 9 to 21. Although aprepitant had no effect on the AUC of norethindrone on day 10, trough concentrations of norethindrone decreased by 60% on days 9 to 21. The effectiveness of hormonal contraceptives is reduced during treatment with aprepitant and for 28 days after treatment. An alternative or back-up method of contraception should be used during treatment with aprepitant and for 1 month after the last dose of aprepitant. Midazolam: Following oral administration of aprepitant 125 mg on day 1 and 80 mg daily on days 2 to 5, and a single oral dose of midazolam 2 mg on days 1 and 5, aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on day 1 and 3.3-fold on day 5. The potential for increased plasma concentrations of midazolam or other benzodiazepines metabolized by CYP3A4 (alprazolam, triazolam) must be considered when coadministering aprepitant (125 mg/80 mg) with these drugs. In another study of midazolam, IV, aprepitant 125 mg was administered orally on day 1 and 80 mg daily on days 2 and 3, and midazolam 2 mg was administered IV prior to the 3-day aprepitant treatment and on days 4, 8, and 15 of aprepitant treatment. Compared to the aprepitant treatment period on days 1 to 3, aprepitant increased the AUC of midazolam by 25% on day 4 and decreased the AUC of midazolam by 19% on day 8. These effects are not clinically important. The AUC of midazolam on day 15 was similar to that observed during the baseline period. A study of intravenous midazolam and aprepitant has also been completed. Midazolam 2 mg was given as an intravenous infusion 1 hour after a single oral dose of aprepitant 125 mg. The plasma AUC of midazolam increased 1.5-fold. This effect is not clinically important. Effects of Other Drugs on the Pharmacokinetics of Aprepitant Aprepitant is a substrate of CYP3A4; therefore, coadministration of aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Therefore, caution is warranted when coadministering aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole); however, coadministration of aprepitant with moderate CYP3A4 inhibitors (e.g., diltiazem) did not result in clinically significant changes in aprepitant plasma concentrations. Aprepitant is a CYP3A4 substrate; therefore, coadministration of aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin) may result in decreased aprepitant plasma concentrations, potentially leading to reduced efficacy of aprepitant. Ketoconazole: When a single oral dose of 125 mg aprepitant was administered on day 5 of a 10-day course of ketoconazole 400 mg daily, the AUC of aprepitant increased approximately 5-fold, and the mean terminal half-life of aprepitant was prolonged approximately 3-fold. Caution is warranted when coadministering aprepitant with strong CYP3A4 inhibitors. Rifampin: When a single oral dose of 375 mg of aprepitant was administered on day 9 of a 14-day course of treatment with the strong CYP3A4 inducer rifampin 600 mg daily, the AUC of aprepitant decreased approximately 11-fold, and the mean terminal half-life decreased approximately 3-fold. Coadministration of aprepitant with drugs that induce CYP3A4 activity may result in decreased plasma concentrations of aprepitant and reduced efficacy. Other Interactions Diltiazem: In patients with mild to moderate hypertension, oral administration of aprepitant tablets similar to the 230 mg capsule formulation once daily with diltiazem 120 mg three times daily for 5 days resulted in a 2-fold increase in the AUC of aprepitant and a 1.7-fold increase in the AUC of diltiazem. These pharmacokinetic effects did not result in clinically significant changes in the electrocardiogram, heart rate, or blood pressure beyond those caused by diltiazem alone. Paroxetine: Coadministration of aprepitant tablets similar to 85 mg or 170 mg capsules once daily with paroxetine 20 mg once daily resulted in an approximately 25% decrease in the AUC of aprepitant and paroxetine and an approximately 20% decrease in Cmax.